The need for postoperative organic support is associated with patient outcomes. Biomarkers may be useful for detecting patients at risk. MR-ProADM is a novel biomarker with an interesting profile that can be used in this context. The main objective of this study was to verify whether there was an association between the preoperative serum levels of MR-ProADM and the need for organic support after elective abdominal cancer surgery, and to determine the preoperative MR-ProADM value that predicts the need for postoperative organic support. This was a multicenter prospective observational study conducted by four tertiary hospitals in Spain between 2017 and 2018. Plasma samples were collected for the quantification of MR-ProADM from adults who underwent major abdominal surgery during 2017–2018. The primary outcome was the need for organic support in the first seven postoperative days and its association with the preoperative levels of MR-ProADM, and the secondary outcome was the preoperative levels of MR-ProADM in the study population. This study included 370 patients with a mean age of 67.4 ± 12.9 years. Seventeen percent (63 patients) required some postoperative organic support measures in the first week. The mean preoperative value of MR-ProADM in patients who required organic support was 1.16 ± 1.15 nmol/L. The AUC-ROC of the preoperative MR-ProADM values associated with the need for organic support was 0.67 (95% CI: 0.59–0.75). The preoperative MR-ProADM value, which showed the best compromise in sensitivity and specificity for predicting the need for organic support, was 0.70 nmol/L. The negative predictive value was 91%. A multivariate analysis confirmed that a preoperative level of MR-ProADM ≥ 0.70 nmol/L is an independent factor associated with risk of postoperative organic support . Elevated preoperative MR-ProADM levels are associated with the need for postoperative organic support. Therefore, MR-ProADM may be a useful biomarker for perioperative risk assessment. Based on data collected from patients after non-cardiac surgery, the European Surgical Outcomes Study (EuSOS) reported a postoperative mortality rate of 4% . In mostThe preoperative identification of at-risk patients is crucial for proposing evidence-based selective actions aimed at reducing the incidence of complications and mortality. The most widespread practice for identifying at-risk patients is the use of prognostic indices and preoperative risk-assessment scales .However, there may be a “clinically silent” disease that is reflected only by elevated plasma biomarker levels and is associated with increased mortality. Preoperative determination of these biomarkers can improve the ability to predict complications, allowing for precise and dynamic risk stratification throughout the perioperative period ,6.Current research is directed towards the use of biomarkers . The preRegional-ProAdrenomedullin (MR-ProADM) is a pro-peptide biomarker of adrenomedullin, a peptide synthesized in several tissues, including the bone, adrenal cortex, kidney, lung, heart, and vessels. The biological effects include vasodilation, inotropism, natriuresis, and bronchodilation .MR-ProADM is a marker of the severity of a wide spectrum of pathological conditions . Elevated plasma levels are associated with hemodynamic and cardiovascular dysfunctions . InteresThe usefulness of MR-ProADM as a predictor of morbidity and mortality in surgical patients has yet to be elucidated.The main objective of this study was to verify whether there is an association between the preoperative serum levels of MR-ProADM and the need for postoperative organic support (POS) after intermediate- and high-risk elective abdominal cancer surgery, and to establish a preoperative MR-ProADM value with the best sensitivity and specificity compromise to predict the need for POS.The secondary objectives were to characterize the preoperative levels of MR-ProADM in a population of patients scheduled for intermediate- and high-risk abdominal cancer surgery, and to determine the association between MR-ProADM and perioperative variables such as age, ASA classification, Revised Cardiac Risk Index (RCRI), POSSUM, and Surgical Apgar Score (SAS) index.This multicenter, prospective, observational study was conducted between February 2017 and May 2018 at the University Hospital of La Princesa , Hospital Clínico Universitario , Hospital del Mar (Barcelona), and Hospital Universitario de la Paz (Madrid).This study recruited consecutive adult patients older than 18 years scheduled for high- and intermediate-risk elective oncological abdominal surgery, according to the Guidelines on Cardiovascular Surgery .Exclusion criteria were patients undergoing low-risk abdominal surgery and patients who did not provide informed consent.A pilot study was conducted at the University Hospital of La Princesa to assess the capacity of MR-ProADM to predict the risk of needing POS.Based on the results, it was determined that it was necessary to recruit a minimum of 55 patients in each group, accepting an α risk of 0.05, and a capacity of 80% to detect differences.Pre-operative plasma samples were collected before anesthesia induction to quantify MR-ProADM. Measurement was made with TRACE technology (Time Resolved Amplified Cryptate Emission) using a new immunoassay sandwich , with a detection limit of 0.05 nmol/L .All samples were analyzed in the Clinical Analysis Laboratory of the University Hospital of La Princesa. The samples obtained at the Hospital del Mar, Clinical Hospital, University of Valladolid, and Hospital Universitario La Paz were frozen and subsequently transferred to the University Hospital of La Princesa to determine the levels of MR-ProADM.We collected preoperative clinical and epidemiological variables including age, sex, ASA classification, RCRI , POSSUM Postoperative organ failure was defined as the presence of at least one of the following conditions: need for administration of amines after volume resuscitation for at least 12 h, need for invasive or non-invasive ventilation not related to sedation and for at least 12 h, and need for new requirements of RRT . The length of the hospital stay and mortality during the first 30 postoperative days were recorded.2 test or Fisher’s exact nonparametric test were used for comparisons. For quantitative variables, the mean was calculated with its standard deviation (SD), and comparisons were made using Student’s t-test or the nonparametric Mann–Whitney U test.For the descriptive analysis of qualitative variables, frequencies were calculated, and Pearson’s χTo select the best discriminatory value of MR-ProADM for the diagnosis of postoperative organ failure, the areas under the ROC curves (AUC) of the mean, median, and mode were compared. The sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), positive likelihood ratio (PVR), negative likelihood ratio (NRV), and probability of correct diagnosis were calculated for MR-ProADM with a higher AUC.Finally, using the selected MR-ProADM values, an explanatory model of postoperative organ failure was constructed using a multivariate logistic regression analysis. Based on a saturated model, a backward phasing strategy was used until the final model was reached, and odds ratios (OR) corresponding to the model variables were calculated. Goodness of fit was assessed using the Hosmer–Lemeshow test.p < 0.05.Data analysis was carried out using the statistical software SPSS version 19.0 for Windows and EPIDAT version 4.2. Differences were considered statistically significant at A total of 373 patients were included in this study. Three patients were excluded because a sample analysis was impossible, leaving 370 valid patients who met the criteria and from whom complete data were collected.The mean age of the patients was 67.4 ± 12.9 years, and 62.2% (230) were older than 65 years. The sample was 65.4% (242) male and 34.6% (128) female. The mean duration and frequency depending on the type of surgical procedure performed are shown in .Regarding the risk scales analyzed, 57.3% (212) presented a score of ≤ 2 in the preoperative ASA classification, whereas in 42.7% (158), the score was ≥ 3. The preoperative RCRI score was 1 point in 77.6% of the patients (287) and ≥ 2 points in the remaining 22.8% (83). The mean POSSUM score was 29,74 points. In total, 49.5% of patients (183) had a score higher than 28 points on this scale. Regarding the SAS score, 8.6% (32) had a score ≤ 4, while 81.4% (338) had a score ≥ 5 points.The mean length of hospital stay was 16.5 ± 33 days. The mortality rate during the first 30 postoperative days was 8.6% (N = 32). Seventeen percent (n = 63) required organ support measures in the first week after surgery. The incidence in the total population, according to the type of POS measure used, is shown in .p < 0.05).The mean preoperative value of MR-ProADM in patients who required POS was 1.16 ± 1.15 (nmol/L), which was significantly higher than that of those who did not require it, with a mean value of 0.74 ± 0.46 (nmol/L) (The area under the ROC curve (AUC-ROC) of the preoperative MR-ProADM values associated with the need for POS was analyzed, obtaining an AUC-ROC of 0.67 (95% CI: 0.59–0.75) .The preoperative MR-ProADM value, which showed the best compromise in sensitivity and specificity in the AUC-ROC for predict the need for POS, was 0.70 nmol/L.The analysis of the diagnostic characteristics of preoperative levels of MR-ProADM ≥ 0.70 nmol/L is described in detail in With the diagnostic characteristics described in For the MR-ProADM value ≥ 0.70 nmol/L as the cut-off point, the negative predictive value obtained was 91%. None of the patients with preoperative MR-ProADM value ≤ 0.25 nmol/L required POS.In the univariate analysis performed to determine perioperative variables associated with need for POS, preoperative MR-ProADM levels ≥ 0.70 nmol/L, age, type of surgery, POSSUM Index, and SAS score were significantly associated with POS .To adjust for possible confounding factors, a multivariate analysis was performed using logistic regression. This analysis included all perioperative variables that showed a statistically significant association with the need for POS in univariate analysis. The results are presented in The multivariate analysis confirmed that the preoperative level of MR-ProADM ≥ 0.70 nmol/L was found to be an independent factor associated with the risk of needing POS; these patients had a 2.6-times-higher risk of POS than those with lower levels. This association was independent of age, sex, type of surgery, and the perioperative risk scale score.The mean preoperative value of MR-ProADM in the 370 patients studied was 0.81 ± 0.65 nmol/L, with a median of 0.66 nmol/L and an interquartile range (IQR) of 0.33. In total, 7.6% (28) of patients had a preoperative MR-ProADM value < 0.4 nmol/L.p < 0.05). Likewise, a significant association (p < 0.05) was found between preoperative MR-ProADM levels ≥ 0.70 nmol/L and the following risk scales: RCRI ≥ 2, ASA ≥ 3, and Possum index ≥ 28. The relationship of the cut-off points of MR-ProADM ≥ 0.70 nmol/L with the perioperative variables was analyzed. The mean age of patients with MR-ProADM levels ≥ 0.70 nmol/L was higher than that of patients with MR-ProADM < 0.70 nmol/L , with ASA value ≥ 3 , and with Possum Index ≥ 28 .The logistic regression analysis found that the presence of preoperative MR-ProADM levels ≥ 0.70 nmol/L was independently associated with age ≥ 65 years .Several studies of scales and biomarkers accepted as risk predictors in other scenarios showed AUC-ROC values similar to our sample .A recent study by Andrés et al.  analyzedIn our sample, the preoperative MR-ProADM value with the best sensitivity and specificity compromise to predict the need for POS was 0.70 nmol/L. In the multivariate analysis, the OR for the prediction of POS with a preoperative MR-ProADM value equal to or greater than 0.70 nmol/L was 2.6. It is important to highlight that the MR-ProADM value < 0.70 nmol/L provided a negative predictive value greater than 90%, which allows us to affirm that, in more than 90% of cases, patients with a preoperative MR-ProADM value < 0.70 nmol/L will not require POS. No patient in the sample with a preoperative MR-ProADM value ≤ 0.25 nmol/L required POS in our series, indicating that healthy patients have a very low probability of complications.Bernal-Morell et al. evaluated the determination of a predictive cut-off point for MR-ProADM in the prediction of organ failure and mortality in patients with sepsis . The cut○A preoperative value of 0.87 nmol/L in the pilot study of our group to predict the need for POS ;○A preoperative value of 0.85 nmol/L in the study by Golubović et al. to predict postoperative mortality in abdominal surgery ;○A preoperative value of 0.77 ± 0.37 nmol/L in the study of Egyed et al. [○A preoperative value of 1.3 nmol/L in the study referring to the prognostic capacity of mortality after TAVI ;○A postoperative value of 3.2 nmol/L in the study for the prediction of mortality in the postoperative period of cardiac surgery .In published studies referring to the predictive value of the perioperative values of MR-ProADM, the following cut-off points were obtained:In the study population, the presence of MR-ProADM levels ≥ 0.70 nmol/L was independently associated with age > 65 years, ASA values ≥ 3, and a POSSUM score ≥ 28. This association is consistent with the idea that the worse the patient’s clinical status, the more likely it is that the biomarker is elevated, and that it is possibly related to a basal inflammatory state and endothelial dysfunction .The results of this study highlight the usefulness of MR-ProADM as a global risk biomarker in the perioperative period after major abdominal oncological surgery.The profile previously demonstrated by MR-ProADM in scenarios and pathologies other than the surgical patient, shows its usefulness in the prediction and stratification of perioperative risk, resulting in a marker that predicts the absence of need for POS in patients with preoperative values < 0.70 nmol/L, presenting a high negative predictive value (NPV) ,42,43,44This study has several limitations regarding the usefulness of MR-ProADM for the prediction of POS in the postoperative period after major abdominal oncological surgery. This was an observational study with inherent limitations. Although this was a multicenter study, there were differences in patient recruitment, with almost half originating from a single center, a minority from another, and almost the other half distributed among the other two participating centers.These limitations, in addition to the possibilities offered by this study, imply the need for more studies to determine the role of MR-ProADM in perioperative risk stratification.Elevated preoperative MR-ProADM levels are associated with the need for POS. The preoperative value of the MR-ProADM, with the best compromise in sensitivity and specificity for predicting the need for POS, was 0.7 nmol/L. Preoperative values of MR-ProADM lower than 0.70 nmol/L significantly rule out the need for POS. Preoperative levels of MR-ProADM ≥ 0.70 nmol/L were independently associated with other variables related to increased perioperative risk.


In addition, when the co-crystals are soaked in tetrahydrofuran, some of the PBA chains are extracted out, leading to damage to the correlative PBS extended-chain crystals. This study shows that co-inclusion complexation with small molecules could be an effective way to promote co-crystallization behavior in polymer blends.Crystalline/crystalline blends of polymer have shown advantages in the preparation of new polymeric materials. However, the regulation of co-crystallization in a blend is still full of challenges due to the preferential self-crystallization driven by thermodynamics. Here, an inclusion complex approach is proposed to facilitate the co-crystallization between crystalline polymers, because the crystallization process displays a prominent kinetics advantage when polymer chains are released from the inclusion complex. Poly(butylene succinate) (PBS), poly(butylene adipate) (PBA) and urea are chosen to form co-inclusion complexes, where PBS and PBA chains play as isolated guest molecules and urea molecules construct the host channel framework. The coalesced PBS/PBA blends are obtained by fast removing the urea framework and systematically investigated by differential scanning calorimetry, X-ray diffraction, proton nuclear magnetic resonance and Fourier transformation infrared spectrometry. It is demonstrated that PBA chains are co-crystallized into PBS extended-chain crystals in the coalesced blends, while such a phenomenon has not been detected in simply co-solution-blended samples. Though PBA chains could not be totally accommodated in the PBS extended-chain crystals, their co-crystallized content increases with the initial feeding ratio of PBA. Consequently, the melting point of the PBS extended-chain crystal gradually declines from 134.3 °C to 124.2 °C with an increasing PBA content. The PBA chains playing as defects mainly induce lattice expansion along the  Blending is a popular way to regulate polymer properties and, thus, optimize materials with desired performance. Currently, a kind of common polymer blend is a crystalline/crystalline system, which consists of two components with different melting and crystallization temperatures, leading to diversified crystallization behaviors and crystal structures ,2,3. Meaco-3-hydroxyvalerate) (PHBV) and poly(3-hydroxybutyrate-co-3-hydroxypropionate) (PHBP) with the same crystallizable poly(3-hydroxybutyrate) (PHB) composition were confirmed to successfully gain co-crystallization [b-polyethylene-b-poly(vinyl cyclohexane) (PVCH-PE-PVCH) [b-polybutadiene (PEO-PB) [To realize effective co-crystallization in the polymer blends, some strategies have been proposed and verified. Blends of poly  and a bl(PEO-PB) . Additio(PEO-PB) ,11,12,13(PEO-PB) . Even th(PEO-PB) , the sim(PEO-PB) . In the (PEO-PB) . Formingl-lactic acid) (PLLA) [aPHB)/PCL [Tg) during the first heating measurement and recovered to two distinct Tgs in the follow-up measurement.The inclusion complex is a specified host/guest supramolecular structure in which polymer chains are isolatedly located as guest molecules in the channels of the host molecule ,19. When) (PLLA) , polycar) (PLLA) , atacticPHB)/PCL , poly(etPHB)/PCL , PC/polyPHB)/PCL , PC/PMMAPHB)/PCL  and PC/PPHB)/PCL . These ad-lactic acid) with thiourea was prepared, and it was found that the formation of stereocomplex crystals of PLLA/PDLA was significantly promoted when the guest chains were released and coalesced [In our previous study, the co-inclusion complex of PLLA and poly at 80.9 °C and 25.0 °C, respectively. Thus, the exothermic Tcs at around 80 °C in DSC curves ii–v were originated from the PBS components in the simply-blended samples; and those Tcs, at around 19 °C in curves iii–v, were ascribed to the PBA components. The decline in Tc of PBA was due to the crystallization confinement caused by the PBS crystals [Conventional DSC investigation. A non-isothermal DSC measurement can reveal the crystal information and crystallization behavior of components in the polymer blends. As shown in crystals . The cryTms) at about 114 °C, which was independent of the blend composition and close to that of neat PBS (114.8 °C). The PBA components in the blends displayed Tms within 50–60 °C, which were slightly lower than that of the neat PBA due to the confinement effect. So, both PBS and PBA should, respectively, form their own crystals in the blends. The crystal structure of PBS was hardly disturbed after being simply blended with the minority PBA, which was further confirmed in the X-ray investigation section.During the subsequent heating process B, the PBTm at around 143 °C each, which were the same as the previously reported Tms of polyester/urea inclusion complexes [Tm at 134.0 °C, which was significantly higher than the raw PBS and could be ascribed to the extended-chain crystals [Tm of the PBS crystal dropped gradually in the coalesced PBS/PBA-90/10 (132.8 °C) and the coalesced PBS/PBA-80/20 (131.9 °C). With an increased content of PBA, the depression of Tm became more obvious. The coalesced crystals of PBS/PBA-70/30 and PBS/PBA-60/40 even displayed Tms at 126.1 °C and 124.0 °C, respectively, together with an apparent shoulder of 114 °C, which was assigned to the common lamellar crystals of PBS. That was, the increase of PBA not only lowered the Tm of the PBS extended-chain crystals but also led to the formation of lamellar crystals of PBS.The DSC curves of the as-prepared inclusion complex in omplexes . There wcrystals . When soTm range of ~50–60 °C, which can be assigned to the melting of the PBA crystals. However, curve ii does not, indicating the absence of PBA crystals in the coalesced PBS/PBA-90/10 sample. Compared with the simply-blended samples (cf. Hm) demonstrated the remarkable depressing formation of the PBA crystal  of the simply-blended samples are shown in 6 °C of tTo eliminate the overlapping of the PBA diffraction signal on PBS, the diffractograms of the simply-blended samples were measured at 70 °C B, at whia-axis.To eliminate the overlapping effect from the PBA crystals, diffractograms of the coalesced blends were measured at 70 °C B. It was1H NMR spectra of the remaining structures were employed to detect the chemical compositions. As shown in Soaking investigation. THF is a good solvent for PBA but a bad solvent for PBS. So, the coalesced blends were soaked in THF long enough  to remove the PBA components as much as possible, the remaining structures were separated and dried in a vacuum oven at room temperature for 48 h for further measurement. The Hm,l), as shown in Hm,l are tabulated in Hm,l increased after soaking, for example, the ΔHm,l of the coalesced-PBS/PBA-60/40 was raised by ~32% (from 23.8 J/g to 31.5 J/g). The only plausible explanation for the increasing PBS lamellar crystal is that some PBS extended-chain crystals were destroyed and re-crystallized into lamellar crystals when part of the PBA chains, accommodated in the PBS extended-chain crystals, were extracted out during soaking in THF.The DSC investigation of the coalesced PBS/PBA blends after soaking was also carried out. As shown in Tm of the PBS extended-chain crystal increased by 0.1–4.4 °C after soaking  is active with polyesters and has the ability to clip the polyester chain structure because it can attack the carbonyl carbon atoms in the polyester chain. MA molecules convert the ester bond into an amide bond, thereby severing the molecular chain . So, MA –1 grew with the initial PBA content, which was close to that of C=O stretching vibrations of the amorphous PBA at 1735 cm–1. It was impossible for the existence of a free amorphous PBA after the MA etching. So, the remaining PBA could only locate the PBS crystalline structure, that is, the PBA chains were co-crystallized with the PBS. The slight shift of the PBA band might be due to the change in the surrounding chemical environment from the amorphous PBA (for the neat sample) to the crystalline PBS .The spectrum of the coalesced PBS/PBA-90/10 after etching was almost the same as the etched PBS A but shoMaterials. The Poly(butylene succinate) (PBS) was supplied by Xinjiang Blue Ridge Tunhe Sci.& Tech. Co. in Changji City, China and the Poly(butylene adipate) (PBA) was prepared through a two-step reaction of esterification and polycondensation in a melt state in the laboratory. Chloroform (AR grade), methanol (AR grade), tetrahydrofuran , hexafluoroisopropanol  and methylamine (40% aqueous solution) were all purchased from Shanghai Aladdin Reagent Co. in Shanghai City, China.g rpm for 20 min to remove any impurity. The clear solution was separated and precipitated with an excess amount of cold methanol, and the precipitates were collected and dried in a vacuum oven at 50 °C for 24 h. The viscosity-average molecular weights (Mη) of PBS are determined as 89.0 kg/mol and the number-average molecular weights (Mn) of PBA are determined as 38.0 kg/mol.Both PBS and PBA were purified through a general procedure before being used. Polyester was first dissolved in chloroform to form a 5 wt% solution, then the solution was centrifuged at a rate of 10,000× w/v). The mole ratios of the urea to the repeated units of PBS and PBA were 0.83:0.17 and 0.85:0.15, respectively [Preparation of polyester/urea inclusion complex. The solution for electrospinning was obtained by dissolving the PBS and PBA with different mole ratios and the urea together in HFIP with a total polyester concentration of 5%  with different proportions. The solutions were stirred at room temperature for 48 h, and then the solvent was evaporated to obtain the simply-blended PBS/PBA samples.Simply-blended PBS/PBA. The controlled samples for comparison were obtained through a solution-mixing process. The PBS and PBA were dissolved in HFIP at a concentration of 5%  measurement. The thermal properties of the samples were measured on a NETZSCH 204F1 differential scanning calorimeter (DSC) equipped with an intercooler system under a nitrogen atmosphere. The instrument was calibrated with indium standard before measurement and operated with a constant flow (40 mL/min) of ultrapure nitrogen gas. All the samples were encapsulated in aluminum DSC pans, and each sample weighed about 5.0 mg.−1.Fourier transformation infrared spectrometer (FTIR) measurement. The samples were ground into a fine powder, together with potassium bromide, in a mortar and placed into a powder tablet machine to form tablets. Spectra were recorded on a Bruker Hyperion spectrometer by averaging signals over 32 scans in the wavenumber range of 4000−800 cmKα radiation source (λ = 0.7093 Å). The samples were raised to the target temperature at a rate of 10 °C/min and held for 3 min before testing. Data were collected in the 2θ interval from 5° to 25° with a scanning rate of 2°/min and a scanning step of 0.01°.Wide angle X-ray diffractometer (WAXD) measurement. Profiles of the polyester samples were in-situ measured on a Rigaku 007HF diffractometer using a Mo 1H NMR) measurement. The 1H NMR spectra of samples were measured on JNM-ECA 600M with chloroform-d (CDCl3) as the solvent and tetramethylsilane (TMS) as the standard.Proton nuclear magnetic resonance (a-axis and the melting point of the PBS extended-chain crystal gradually declined from 134.3 °C to 124.2 °C with increasing the PBA content. In addition, when the co-crystals were soaked in tetrahydrofuran, some of the PBA chains were extracted out, leading to the damage of the correlative PBS extended-chain crystals. This study shows that co-inclusion complexation with small molecules could be an effective way to promote co-crystallization in polymer blends.In this study, crystalline/crystalline polymer blends of PBS/PBA were fabricated through an approach of co-inclusion complexation with urea molecules and investigated using DSC, WAXD, NMR and FTIR. It is demonstrated that the PBA chains were co-crystallized into PBS extended-chain crystals in the coalesced blends and the co-crystallized content increases with the initial blending ratio of the PBA. The PBA chains playing as defects mainly induced lattice expansion along the


CI 0.72; 95%CI 0.53–0.99). Causal mediation analysis suggests that the higher rate of RR-TB treatment initiation in people diagnosed by the Xpert assay explains the effect of Xpert on 2-year mortality , 42.7% died. Of these, 364 (48.6%) patients died in the pre-Xpert group and 200 (39.8%) in the Xpert group. People diagnosed with RR-TB by the Xpert assay had a higher odds of RR-TB treatment initiation compared to those diagnosed by the targeted LPA-based diagnostic process . Receiving an RR-TB diagnosis by Xpert resulted in a 28% reduction in the odds of mortality within 2 years after presentation to the clinic (OR IPTW thus creates a hypothetical pseudo-population twice as large as the observed study population, where each individual appears both as exposed and unexposed. By doing so, the marginal risk of experiencing the outcome  under a diagnosis  is independent of the actual method of diagnosis received in the observational study ,36–40 F. This prAfter applying both IOSWs and IPTWs, we estimated the OR of RR-TB treatment initiation in the Xpert population versus the pre-Xpert population and the total effect of having a diagnosis made by Xpert on  2-year mortality. Properties of the different weights can be found in the We hypothesized that the proportion of people who initiate RR-TB treatment may be higher among people diagnosed with RR-TB by the Xpert assay and that this mediator could explain the effect of the Xpert assay on RR-TB mortality . To asseWe performed the analysis using a weighting-based approach (ratio of mediator probability weighting) to create a pseudo-population. In this hypothetical population, each individual has an outcome  and mediator variable (whether RR-TB treatment was initiated or not) as was observed in the data , as well as a counterfactual outcome and mediator value, which would have occurred if the individual had been diagnosed with the diagnostic algorithm (pre-Xpert or Xpert) other than the one they were diagnosed with in the observational study.Using this ‘pseudo-population’ dataset, a natural effect model was then applied using the R package Medflex, to estimate the natural indirect effect (NIE) , which i2 (SD 6.2). Half (52.2%) of all patients had a history of TB treatment, and 17.7% (n = 133) patients reported another predictive factor for RR-TB [close contact with an MDR-TB patient (n = 111) or working at a healthcare facility (n = 22)]. Most (78%) patients were living with HIV, of whom only one in three (33%) were on ART.The EXIT-RIF observational cohort study (Jan 2012- Dec 2013) enrolled 749 RR-TB patients of which 247 (33%) were diagnosed with RR-TB by the pre-Xpert diagnostic process and 502 (67%) by the Xpert assay. Patients were diagnosed in three South African provinces: Gauteng , Free State , and Eastern Cape  . BecauseCompared to patients diagnosed by Xpert, more patients diagnosed in the pre-Xpert period were smear positive (47% vs 38%), had been treated for TB before (60% vs 48%) with default (29% vs 18%) or failure (7% vs 3%) during their prior treatment episode. The distribution of province and ART status also differed between the two groups. Crude 2-year mortality was 48.6% in the pre-Xpert group and 39.8% in the Xpert period.CI 0.72; 95%CI 0.53–0.99)  was 0.90 (95%CI 0.85–0.96). The estimate of the natural direct effect OR  was lower (0.80) but the 95% CI crossed 1 (95%CI 0.59–1.10). These results suggest that the higher rate of treatment initiation modifies the effect of Xpert on 2year mortality, and that the effect of Xpert on 2-year mortality compared to the pre-Xpert diagnostic algorithm may be due to higher rates of RR-TB treatment initiation.When applying IOSW, IPTW and MSM for causal inference, we found that receiving an RR-TB diagnosis by Xpert reduced 2-year mortality (OR53–0.99) . This reCI 0.72; 95%CI 0.53–0.99) among people who presented to a health facility with symptoms of TB due to RR-TB. Moreover, the presence of a natural indirect effect  suggests that the total effect of Xpert on mortality is mostly due to an effect of the Xpert assay on RR-TB treatment initiation rather than a direct effect of the diagnostic itself. Taken together, we show that, among people with signs and symptoms of TB (due to RR-TB) presenting to a clinic, the use of the Xpert assay causes a reduction in mortality, mainly through an increase in RR-TB treatment initiation.In this study, we found that use of the Xpert assay causes an increase in odds of starting RR-TB treatment (OR 2.79 95%CI 2.19–3.56) and a reduction in the 2-year odds of death  TB ,43. The Another important strength of our study relates to the quality of the observational data used to emulate the hypothetical RCT. The EXIT-RIF study was a prospective cohort study aimed at determining the association between the implementation of Xpert and mortality in people diagnosed with RR-TB. The use a of centralized laboratory system to determine eligibility allowed the study to include all patients diagnosed with RR-TB in three provinces, not only those who present for RR-TB care at selected study sites which is common in many studies of RR-TB. The detailed collection of data on 2-year mortality though multiple sources resulted in complete data which allowed us to accurately assess the effect of Xpert on 2-year mortality, even for those lost to RR-TB care.A limitation of the study is that we did not account for missing data in covariates. We do not believe that this greatly biased the results as none of the variables included in the analyses had missingness greater than 11%. Moreover, while Xpert’s sensitivity is excellent ±94.4% ,34), it , it 34])In conclusion, using causal inference methods in combination with high quality observational data, we provide a robust answer to a research question of high policy and patient relevance: ‘does the routine use of a new rapid molecular assay result in a reduction in RR-TB mortality?’. Our analysis provides confirmatory evidence that the use of Xpert reduces 2-year mortality among people presenting to the clinic with signs and symptoms of TB due to RR-TB. This highlights the need for advocacy for a continued global roll-out of rapid molecular tests to diagnose TB drug resistance. Furthermore, as mediation analysis showed the effect is mainly due to a higher probability of RR-TB treatment initiation, health care systems should ensure timely initiation of treatment regimens upon diagnosis of RR-TB.S1 FigThe Expected (E) value of the outcome  (Y) under a certain exposure status , and certain mediator value (RR-TB treatment) under a given exposure status .(DOCX)Click here for additional data file.S1 Text(DOCX)Click here for additional data file.


Different levels of duplex microstructure could be achieved along with the process cycles. The grain structure using EBSD analysis showed refined equiaxed grains, which demonstrate better strength after the HT-HIP process. Twinning boundaries were also observed in the HT-HIP sample. The grain orientation tendency to the build direction significantly reduced after the HT-HIP process. The nanoindentation test was applied to evaluate the nanohardness of the as-built and HT-HIP samples. It could be demonstrated that the nanohardness is dependent on the formed phases and lamellar density inside the grains. The mean hardness value was 8.19 GPa for the as-built sample, while it was 5.48 GPa for the HT-HIP sample.Postprocessing is essential for improving titanium aluminide (TiAl) microstructure and part quality after using the laser powder bed fusion (L-PBF) method. It has been reported that Ti-48Al-2Cr-2Nb (%at) processed by L-PBF has internal defects and low fracture toughness. Microstructure control by heat treatment (HT) showed a significant improvement in the ductility of the material. Alternatively, hot isostatic pressing (HIPing) could be applied to reduce the residual stresses and internal defects formed during the L-PBF. Combining the benefits of these two subsequent processes into a single predetermined process is appealing for Ti-48Al-2Cr-2Nb (%at) to minimize cost. This work presents a novel strategy to postprocess L-PBF TiAl by applying combined heat treatment and hot isostatic pressing in one process, namely HT-HIP. The process includes three cycles with different conditions . These conditions were determined to achieve improved part quality and microstructure. The results show that the tensile residual stresses decreased from a peak of 249 MPa in the as-built sample to compressive stresses that peaked at −90 MPa after the HT-HIP process. The number and size of internal defects could be greatly reduced. The defects were transformed into a regular spherical shape, which is good in terms of fatigue strength. Additionally, a duplex microstructure with lamellar α Titanium aluminide (TiAl), Ti-48Al-2Cr-2Nb (%at), is an advanced intermetallic alloy that is widely used in aerospace industry. The combination of high strength and low density makes it superior over other heavy alloys. Its excellent high-temperature performance has promoted the replacement of nickel superalloys by TiAl in low-pressure turbine blades . However3, compared with the other traditional L-PBF strategies. However, some internal defects such as micropores and/or cracks were observed. Thus, the hot isostatic processing (HIP) was highly recommended [As an advanced near-net shape manufacturing technology, laser powder bed fusion (L-PBF) has shown an efficient capability to produce different metals in complex shapes with high geometrical accuracy . This coommended ,16.2 + γ [2 phase, while the γ phase scarcely existed [2 phase increases the alloy strength at the expense of the ductility [2 and γ, arranged in lamellar colonies of coarse grains, which forms at higher annealing temperatures, above and just below the α transus line. The fully lamellar microstructure showed higher tensile strength and creep properties but less ductility [The TiAl mechanical properties mainly depend on the processed microstructure and the HT conditions. The solidification route after thermomechanical processing leads to a microstructure dependent on the cooling rate and alloy composition ,18. This2 + γ . However existed . This wa existed . The domuctility . Therefouctility . In the uctility . The equuctility . The neauctility . The dupuctility .effP is the effective pressure, P is the external pressure, P0 is the outgassing pressure, d is the relative density, d0 is the initial relative density, cd is the relative density at which pores close, r is the particle radius, and spE is the specific surface energy.Hot isostatic pressing (HIP) has been shown to have a significant effect on eliminating internal defects after L-PBF ,28,29. TThe novelty of this study lies in the proposal of a novel postprocessing strategy, HT-HIP, for laser-melted Ti-48Al-2Nb-2Cr (at%). Ti-48Al-2Nb-2Cr (at%) is an important alloy with exceptional properties, enabling the development of lightweight, efficient, and durable components for various industries. Heat treatment (HT) and hot isostatic pressing (HIPing) are crucial processes for optimizing the microstructure and mechanical properties of Ti-48Al-2Nb-2Cr (at%). Heat treatment enhances desired phase formation, strength, and ductility, while HIPing improves density, mechanical properties, and lifespan. Combining these techniques in one process  unlocks the full potential of Ti-48Al-2Nb-2Cr (at%) for advanced materials. Thus, this study presents a new approach to address common issues in Ti-48Al-2Nb-2Cr (at%) processed by L-PBF, such as residual stresses, internal defects, and low ductility. The HT-HIP process combines microstructure improvement and part densification into a cost-effective single process. The proposed method is presented as a multicycle process to investigate the influence of each cycle on the part quality and microstructure formation. The in-depth residual stresses, part defects, microstructure evolution, grain structure, and nanohardness are compared with and without the HT-HIP process. This study makes a significant contribution to sectors that prioritize the development of lightweight, efficient, and durable components, such as aerospace, automotive, and energy industries. By specifically examining the effects of HT-HIP on titanium aluminide, this research effectively tackles the persistent challenges of high residual stresses, internal defects, and low ductility commonly observed in laser-melted Ti-48Al-2Nb-2Cr (at%). The findings directly address these issues, providing valuable insights for improving the performance and reliability of TiAl components in demanding industrial applications.In this study a predefined heat treatment was established along with hot isostatic pressure (HT-HIP) as one process. This combined process was held after processing TiAl by L-PBF under preheating temperature of 200 °C and using sequential thermal scanning (STS) strategy. The HT-HIP included three cycles, as shown in 3) were fabricated using L-PBF under a preheating temperature of 200 °C and using STS strategy, as shown in To study the influence of the HT-HIP process and compare it with the traditional HT method, three TiAl samples (10 × 10 × 7 mmα target was used to diffract from the (213) plane at a diffraction angle (2ϴ) of approximately 149°. The X-ray was targeted to the midpoint of the surface to measure the bidirectional RS. No surface preparation was applied for surface residual stress measurements. Then, the samples were electropolished each time before measuring the depth points to avoid the addition of thermal and/or mechanical stresses. A solution of perchloric acid and methanol was used for electropolishing. The X-ray diffraction residual stress measurements were collected using the multiple exposure technique with a minimum of 22 angles (titling angles) up to 25°. A Gaussian function was used to fit the diffraction peaks. The residual stress measurements were performed using the Proto LXRD stress analyzer.The in-depth residual stresses (RS) were measured for the as-built and HT-HIP samples by a high-speed X-ray diffraction (XRD) machine installed with two detectors , as shown in The surface and internal defects such as pores and cracks were investigated for the as-built and postprocessed samples shown in The microstructure evolution was investigated for the different processed samples using a scanning electron microscope (SEM), TESCAN VEGA SEM . The samples were scanned using the backscattered electron (BSE) mode to distinguish the different phases. Powder diffraction analysis was applied to identify the phases formed in the 3-cycle HT-HIP sample using a Proto AXRD Benchtop powder diffractometer . The data were collected over a wide 2θ range (20°–110°) using Co K-α radiation. The instrument was operated at 35 kV and 30 mA, with a step size of 0.015°, and a dwell time of 8–10 s. In addition, the grain structure was studied using electron backscattered diffraction (EBSD) microscope, FEI Versa 3D Dual Beam SEM/FIB . It was necessary to polish the samples very finely up to 1 µm and then apply OP-S to obtain high-resolution EBSD imaging. TSL OIM Analysis 7   and AztecCrystal software   were used to interpret the EBSD data and analyze the grain size, orientation, dislocation density, and angle grain boundaries. The phase formation in the as-built and HT-HIP sample were also identified using EBSD phase mapping.The nanoindentation test was performed using Anton Paar NHT3 tester . Nanoindentation is typically used to evaluate mechanical properties  at the nanoscale. The results are typically more accurate than the macro- and microtests. Nanoindentation is essential when measuring the multiphase material of fine microstructures, as is the case in the HT-HIP samples. A Berkovich tip with a pyramidal shape was used for making the indentation. The as-built and HT-HIP samples were mounted and polished to be tested on their cross-section surface. The maximum applied load was 15 mN. The indenter was held for two seconds before unloading. The loading/unloading rate was 30 mN/min. The nanohardness (H) and reduced elastic modulus (REM) were calculated from the loading–unloading curves, as elucidated in The high residual stresses (RSs) induced inside fabricated parts are the main cause of crack formation and poor mechanical properties. It is well known that if the RSs exceed the yield value, the sample will fail due to crack formation and propagation. In L-PBF, the RSs are mainly dependent on the thermal stresses induced by the rapid heating and cooling after the L-PBF. It has been reported that TiAl parts usually experience high tensile stresses after the L-PBF process . These hThe bidirectional RSs were measured along the depth of ~1 mm (34 layers) for two samples, with and without the HT-HIP. It was also observed that the RSs in the as-built sample were higher in the X-direction than Y-direction. This agrees with the fact that the thermal gradient is higher in the melt direction than the hatch direction, Y . The higThe mitigation of tensile residual stresses within the as-built sample can be attributed to the influence of heating the underlying layers during the melting of each successive layer. This heat transfer facilitates the release of residual tensile stresses, resulting in a less stressed core within the sample. Notably, In essence, the reduction in residual stresses achieved through the HT-HIP process can be attributed to the high temperature and pressure conditions applied during this postprocessing technique. The elevated temperature during hot isostatic pressing (HIP) facilitates the diffusion of various defects, including voids, dislocations, and porosity, that commonly present in the as-built TiAl parts manufactured using laser powder bed fusion (LPBF). This diffusion process allows the defects to rearrange and heal, resulting in a more uniform microstructure and a reduction in stress concentrations within the material. Moreover, the high pressure exerted during the HIPing process induces compression stresses and plastic deformation in the TiAl material. This plastic deformation enables the redistribution and relaxation of the tensile residual stresses, further contributing to the overall reduction in stress levels within the HT-HIP sample.It is also worth noting that the deviation of the RSs after applying the HT-HIP increased compared with the as-built sample, The main challenge of processing TiAl by L-PBF is the formation of defects such as pores and cracks. These defects are destructive to the part performance under different applications. The pores and cracks are typically classified by the reason of formation. The pores are formed due to lack of fusion, unmolten powder, keyhole mode, and/or gas retention. However, the cracks are typically formed due to solidification shrinkage, elemental segregation, and/or thermal induced stresses. More details about these defects and their causes have been discussed in . The lasThe optical examination of surface defects revealed no substantial reduction following the HT-HIP process. This finding was demonstrated by comparing the top and side surfaces of the as-built and HT-HIPed samples, as shown in P) is increased as the defect radius (r) decreases. Knowing that (γ) is the specific surface energy, the large volume defects would therefore have been expected to shrink exponentially at low pressure, whereas as they decreased in size, a very high pressure would require their complete closure. Therefore, it can be concluded that the temperature and pressure values are essential factors for the HT-HIP process. However, the temperature factor must be carefully selected but not at the expense of the target microstructure, as discussed in the coming section.Defect reduction or elimination via the HT-HIP process can be explained on a microscale by the simultaneous effects of both the material diffusion and transportation mechanisms that can occur under hot isostatic pressure . During 2 [2 phase is the long-range hexagonal-ordered structure that forms below the eutectic point from the disordered α phase. The high strength but poor ductility are characteristics of α2 phase. 3. It can be seen in the figure that the dominant phase was the light gray α2 phase, while a scarce amount of dark gray γ phase was also noted. The dark gray areas noticed along and just below the melt pool boundaries were presumably formed due to the remelting effect and the lower temperature gradient that might allow the Al-rich grains (γ phase) to grow and appear in these spots. A small portion of nearly lamellar α2/γ was also observed, referred to by the red arrow. This agrees with the published studies about the as-built L-PBF microstructure [Processing the microstructure is of great importance for improving material behavior. Grain shape, size, and phase formation are vital factors when controlling the toughness of TiAl parts . It has 2 . The α2 tructure ,9,34. Th2 and γ grains after 1-cycle HT-HIP. Lamellar α2/γ colonies were also observed. This emphasizes that the annealing temperature at 1250 °C, in the α + γ region, could allow the small nucleus of γ to grow and appear significantly with α2 in a dual-phase microstructure. In addition, holding the annealing temperature for 4 h gave rise for the γ grains to diffuse with the α2 in lamellar colonies. Finally, applying uniform rapid cooling (URC) could retain this microstructure at room temperature. The transformation from α to lamellar α+ γ is governed by the nucleation and growth process. Nucleation is typically preferred at the grain boundaries and occurs during the formation of the planar faults in the parent α phase [The effect of the different postprocesses and number of cycles on the microstructure was investigated.  α phase ,56. Ther α phase . This phThe benefit of the proposed HT-HIP is to combine the thermal advantage of the heat treatment to control the microstructure with the mechanical advantage of the HIP process to reduce internal defects. Therefore, it was important to compare the microstructure of a sample postprocessed by HT-HIP with another sample postprocessed by only HT using the same number of cycles. G) and high growth velocity (V) during the L-PBF. This could be attributed to the sequential thermal scanning, which decreases the thermal gradient, as well as the remelting effect, which increases the grain growth rate. It has been well established that the ratio between the thermal gradient and growth velocity (G/V) controls the grain morphology [n/VG and grain morphology [G is the thermal gradient, V is the growth velocity, oN is the nucleation sites/density, n/VG indicates the low volume fraction of equiaxed grains in front of the solid/liquid interface  in the HT-HIPed microstructure. It is also noteworthy that the grain size charts indicate coarse grains in the as-built sample with a maximum size of 39 µm, while fine grains in the HT-HIPed sample have a maximum size of 8.5 µm. Twinning boundaries were also observed in the HT-HIPed sample. This was attributed to the atomic displacement occurred during the plastic deformation associated with the hot isostatic pressure. The relationship between the grain size (d), twin spacing (t), and material strength (yσ) can be demonstrated using the Hall–Petch equation. As indicated in Equation (5), the material yield strength (yσ) increases as the effective barrier spacing (effL) decreases. The effective barrier spacing is directly proportional to the grain size and twin spacing, as shown in Equation (6) [The grain structure was studied for two samples with different postprocessing conditions using EBSD analysis. rphology ,59. Equarphology ,61, in wpressure . Typicaltion (6) . Thus, b2 with 97.7% of the scanned area. In contrast, the dominant phase in the HT-HIPed sample was γ with 94.4%. The α2 and retained beta (B1) phases were also observed in the HT-HIPed sample in low proportions of 4.6% and 1.1%, respectively. The demonstration of these formed phases in the as-built and HT-HIPed samples emphasizes the microstructure analysis discussed in the previous section. It is also worth mentioning that the voids and cracks were excluded from the EBSD analysis (indicated by the black and white dots and lines). However, it was necessary to investigate what kind of crack appeared. The band contrast and grain orientation maps demonstrated transgranular crack type. This indicates that the cracks were formed after the grain formation due to thermal-induced residual stresses.The grain orientation and phase formation in the two samples was investigated. Geometrically necessary dislocations (GNDs) are a type of dislocation that are concentrated in regions where plastic deformation occurs within a crystal lattice . Unlike In L-PBF, grain boundary misorientation angles are typically high (>15°). This is due to the remelting effect, which causes grain recrystallization . Grain rThe nanoindentation test is typically used to determine essential mechanical properties  for delicate microstructure at the nanoscale. It has been reported that the hardness of TiAl samples after post-treatment is phase-dependent . It was 2, γ, and β phases. The nanohardness and reduced elastic modulus values have been reported for these phases in the literature [2, and γ phases were 7.2 GPa, 5.3 GPa, and 4.2 GPa, respectively. The reduced elastic modulus values were 172 GPa for β, 163 GPa for γ, 149 GPa for α2. However, there was a difference in results with other studies [2 phase in the grain. As α2 is harder than γ, the nanohardness values were high. On the contrary, the lowest nanohardness values correspond to points 3, 4, and 5. These points are located in dark gray grains, which refer to lamellar-rich structure of γ phase. Thus, the nanohardness values were the least. Between the highest and lowest hardness points, there were medium gray points at 6 and 7. These points refer to close ratios of the α2 and γ phases in the lamellar structure with medium nanohardness. Oppositely, the reduced modulus of elasticity showed varied values between 139.4 and 194.2. This agrees to great extent with the calculated and experimental results of the elastic modulus reported in the literature for the α2 and γ phases [As demonstrated earlier, the HT-HIP and HT samples contain αterature . The nan studies . This isγ phases . The sam2 phase in the microstructure of the as-built sample. Meanwhile, the reduced modulus of elasticity showed a mean value of 140, lower than the HT-HIP sample of 168.67. Both the H and REM mean values are close to the α2 values reported in the literature, 7.4 GPa and 141 [ and 141 ,66.This study presented a thorough investigation into a novel postprocessing strategy, HT-HIP, for laser-melted Ti-48Al-2Cr-2Nb (at%) alloy. The main objective was to explore the effects of the HT-HIP process on various aspects of Ti-48Al-2Cr-2Nb (at%) samples, including residual stresses, defects, microstructure evolution, and nanohardness.The HT-HIP process involved three cycles with different conditions. The first cycle employed an isothermal heat treatment at 800 °C for 72 h without applying any pressure. The second cycle encompassed an annealing treatment at 1250 °C for 4 h under a pressure of 200 MPa. Finally, the third cycle consisted of an aging treatment at 900 °C for 4 h under a pressure of 150 MPa.By implementing the HT-HIP process, significant improvements were observed in terms of residual stresses. The tensile residual stresses, which were prevalent in the as-built samples, were significantly reduced, and compressive residual stresses were introduced in the HT-HIP samples. This adjustment indicated enhanced planar isotropic strength and a notable reduction in internal defects. The size and quantity of defects decreased substantially.2 phases, along with lamellar colonies, was observed to evolve in varying levels throughout the cycles. Additionally, the presence of the hard B1 phase was detected in the samples subjected to the second and third HT-HIP cycles. The level of duplex microstructure, lamellar colonies, and B1 phase could be controlled through the HT-HIP cycles, allowing for a trade-off between the strength, ductility, and hardness properties. Furthermore, the 3-cycle HT-HIP process achieved a microstructure similar to that achieved with a 3-cycle HT process. However, prolonging the holding time during the isothermal HT cycle in the 3-cycle HT-HIP process could enhance the microstructure homogeneity and the presence of the ductile γ phase.Microstructural analysis revealed noteworthy changes during the HT-HIP cycles. The duplex microstructure consisting of γ and αGrain structure analysis showed that the HT-HIP process leads to significant grain refinement compared with the as-built samples. Furthermore, twinning boundaries were observed in the HT-HIP microstructure, indicating increased strength compared with the as-built counterparts. The orientation of grains along the build direction {0001} observed in the as-built samples was significantly reduced after the HT-HIP process, resulting in a more homogeneous microstructure.2 phase. The variation in nanohardness values of the HT-HIPed samples was attributed to the different levels of duplex microstructure and lamellar colonies within the grains.The nanohardness values of the HT-HIPed samples showed dependency on the formed phases and lamellar density. In contrast, the as-built samples exhibited relatively stable nanohardness values due to the dominant αIn summary, the HT-HIP process demonstrated substantial improvements in terms of the residual stresses, defects, microstructure, and hardness properties of the Ti-48Al-2Cr-2Nb (at%) alloy samples. These findings highlight the potential of HT-HIP as an effective postprocessing strategy for enhancing the performance and reliability of laser-melted Ti-48Al-2Cr-2Nb (at%) components in various industries.


Critical care patients often require central venous cannulation (CVC). We hypothesized that real-time biplane ultrasound-guided CVC would improve first-puncture success rate and reduce mechanical complications. The purpose of this study was to compare the success rate and safety of single-plane and real-time biplane approaches for ultrasound-guided CVC.n = 128) or biplane (n = 128) ultrasound-guided cannulation groups. The success rate, number of punctures, procedure duration, incidence of catheterization-related complications, and confidence score of operators were documented.From October 2022 to March 2023, 256 participants with critical illness requiring CVC were randomized to either the single-plane . The biplane group was also associated with a higher first-puncture single-pass catheterization success rate (87.4% vs. 69.0% and 90.9% vs. 68.3%), fewer undesired punctures (1[1–1(1–2)] vs. 1[1–2(1–4)] and 1[1–1(1–3)] vs. 1[1–2(1–4)]), shorter cannulation time ] vs. 311 s [243–401 ] and 228 s [193–306 ] vs. 340 s [246–499 (130–944)]), and fewer immediate complications (10.5% vs. 28.7% and 9.1% vs. 34.1%) for both IJVC and FVC .The central vein was successfully cannulated in all 256 participants , including 182 and 74 who underwent internal jugular vein cannulation (IJVC) and femoral vein cannulation (FVC), respectively. The incidence of successful puncture on the first attempt was higher in the biplane group than that in the single-plane group , 1.226; 95% confidence interval (CI), 1.069–1.405; Real-time biplane imaging of ultrasound-guided CVCs offers advantages over the single-plane approach for critically ill patients.Trial registration: This prospective RCT was registered at Chinese Clinical Trial Registry (ChiCTR2200064843). Registered 19 October 2022.The online version contains supplementary material available at 10.1186/s13054-023-04635-y. Central venous catheterization (CVC), which can be lifesaving for critically ill patients, is frequently performed to aid the intravenous administration of fluid resuscitation, allow safe intravenous administration of medication, facilitate hemodialysis, and help in the monitoring of hemodynamic variables in the intensive care unit (ICU) , 2. MoreTwo different two-dimensional (2D) US techniques employed for CVCs, including out-of-plane and in-plane approaches, are both single-plane display techniques , 24, 25.The x-plane technique, a real-time three-dimensional (3D) imaging technique, uses a matrix array probe (3–14 MHz) that takes advantage of the strengths and overcomes the limitations of previous approaches, allowing for simultaneous imaging of both transverse and longitudinal views without rotating the probe. Thus, the x-plane approach creates a comprehensive picture of both the needle trajectory and vein with its surrounding structures. To our knowledge, only one study has compared US-guided out-of-plane and biplane imaging for internal jugular catheterization (IJVC) with a low-frequency transducer ; howeverThis prospective, single-center, randomized clinical trial was conducted at The First Medical Center of Chinese PLA General Hospital. The study protocol was approved by the local Ethics Committee and was registered at Chinese Clinical Trial Registry. Written informed consent was obtained from each patient diagnosed with a critical illness requiring CVC between October 2022 and March 2023. A flow diagram of the study is shown in Fig. All CVC procedures were performed for clinical reasons. The decision to perform CVC, either IJVC or FVC, was made by the physician on duty and was not involved in the study. Patients were randomized to the x-plane or single-plane approaches using means of a computer-generated random number table. Vital signs and coagulation indices were recorded.Each cannulation was performed at the patient’s bedside by one of five sonographers with three months of experience in US-guided CVC. They had similar experience with x-plane and single-plane cannulations . Two-lumen 7F, 20 cm-long CVCs  were used for infusion and dual-lumen 13.5F, dialysis catheters  were used for dialysis.A Philips  CX50 system equipped with a L12-3 probe and an EPIQ system equipped with a XL14-3 probe were used for single-plane and x-plane CVCs, respectively. The CVCs were performed following previously recommended steps . The priThe puncture site was prepared using antiseptic solution and protected with sterile drapes, whereas the probe was covered with a sterile sheath using sterile gel outside and inside the sheath. A real-time, single-operator, freehand technique was used. While introducing the needle, the operator held the probe with one hand, and the needle with the other hand, lidocaine 2% was used to anesthetize the puncture site, followed by needle puncture into the vein with the modified Seldinger technique.The single-plane approach was performed under the guidance of the long-axis view of the vein using in-plane method. The needle was held at 30°–45° angle, oriented in-plane with transducer. Vessel alignment was maintained during the procedure, and the entire length of the needle was visible during progression through the tissues.Using the x-plane approach, the vein was visualized simultaneously in transverse and longitudinal images. The probe was positioned as the single-plane approach, maintaining the vein in the middle of both the long- and short-axis views. During the procedure, the entire length of the needle was visible in-plane in the long-axis view, and the transient vessel deformation produced by the additional pressure when the tip abutted the venous wall was observed in the short-axis view. Once the vessel wall was penetrated, the deformation disappeared and a hyperechoic dot was displayed within the vein in the short-axis view.In both single- and x-plane approaches, the presence of the needle in the vein was confirmed by aspiration of blood into the syringe. When the needle tip was inserted into the vessel, the assistant advanced the guidewire. The needle was withdrawn, a dilator was used, and a catheter inserted as usual , hematoma, posterior venous wall puncture, arterial puncture, pneumothorax, and hemothorax and late complications such as venous thrombosis and central line-associated blood stream infection (CLA-BSI) within 30 days after cannulation; and operator confidence score.Puncture time was defined as the period between skin penetration by the needle and the first flashback of blood. The total catheterization time was defined as the period between the probe positioning on the patient’s skin and insertion of the catheter. The operator confidence score was graded according to their degree of confidence during the CVC procedure: 1-point, lack of confidence in the first puncture success; 2-point, intermediate grade; 3-point, very confident in the first puncture success.The sample size was calculated assuming that the first-needle-puncture success rate was 0.75 in the single-plane group based on previous studies, which reported success rates of 52–85.5% when using single-plane US-guided technique in IJVC and FVC , 29–31. t-test, Mann–Whitney U-test, Chi-square test, or Fisher’s exact test were used where appropriate to identify differences between the two groups for continuous or categorical variables. The probability of lack of complications after CVC positioning was calculated using the Kaplan–Meier product-limit estimator. The log-rank (Mantel-Cox) test was used to evaluate the difference in the probability of lack of complications after grouping for the single-plane versus x-plane approach. Statistical significance was set at a P value < 0.05. Statistical analyses were performed using PASS , SPSS , and GraphPad Prism .Data are expressed as median, interquartile range (IQR), range, count number, or percentage, as indicated. The Kolmogorov–Smirnov test was used to evaluate the normal distribution of continuous variables. Unpaired Student’s Catheter positioning was possible in all 256 patients using either the single- or x-plane approach. The baseline characteristics and the ultrasonographic characteristics of the study population are summarized in Table P = 0.002; and 90.9% vs. 68.3%; RR, 1.331; 95% CI, 1.053–1.684; P = 0.019 for IJVC and FVC, respectively]. In addition, the number (median [IQR (range)]) of puncture attempts was lower in the x-plane group than that in the single-plane group (1[1–1(1–2)] vs. 1[1–2(1–4)]; P < 0.001 and 1[1–1(1–3)] vs. 1[1–2(1–4)]; P = 0.029 for IJVC and FVC, respectively). The total CVC time in seconds was shorter in the x-plane group than in the single-plane group ] vs. 311 [243–401 ]; P < 0.001 and 228 [193–306 ] vs. 340 [246–499 (130–944)]; P < 0.001 for IJVC and FVC, respectively), as well as the puncture time. A higher confidence score of the operator during the CVC procedure after the x-plane guidance (2 [2–3 (1–3)] vs. 2[1–2(1–3)]; P = 0.008 and 3 [2–3 (1–3)] vs. 2[2–2(1–3)]; P < 0.001 for IJVC and FVC, respectively) was statistically significant.The procedural data are summarized in Table P = 0.002 and 14/41 (34.1%); RR, 0.266; 95% CI, 0.083–0.849; P = 0.011 for IJVC and FVC, respectively].The incidence of immediate complications was lower in the patients undergoing x-plane-guided catheterization  compared with those undergoing single-plane catheterization [25/87 (28.7%); RR, 0.366; 95% CI, 0.187–0.718; P = 0.352 and P = 0.124 for IJVC and FVC, respectively  and FVC (90.9% vs. 68.3%), although the overall success rate for US-guided CVCs was 100%. The higher first-puncture success rate, fewer puncture attempts, and shorter catheterization time were mainly attributed to the advantages of the x-plane approach, which overcame the limitations of the single-plane approach and allowed users to visualize both the transverse and longitudinal views simultaneously.The real-time biplane imaging technique offers visualization of the trajectory of the needle tip, which was confirmed by the long-axis view, and the confirmation of the needle tip inside the lumen, as well as the relationship of the target vessel to adjacent structures, which was offered by the short-axis view. This explains the higher first-puncture success rate  and shorter time  needed for CVCs in the x-plane group than that in the single-plane group. Meanwhile, the confidence score of the operator during the cannulation procedure was higher in the x-plane group , which could be another reason for the shorter catheterization time. Our results prove that the biplane approach optimizes the chances of successful cannulation and minimizes the risks to the surrounding structures.The higher incidence of immediate complications in the single-plane approach  was mainly due to undesired punctures with multiple skin breach to redirect the needle. This is explained by the fact that the operator cannot line up the thin US beam with the entire length of the needle, and both have the midline axis of the vessel longitudinal plane. During CVC positioning, the hand of the operator can slide by a few millimeters, and the three axes can move out of alignment with each other, thus allowing visualization of the artery. In this context, information regarding the location of the artery and target vein is lost, and the continuous display of the needle leads to a misleading sense of safety that may ultimately lead to redirection and repuncture of the needle, as well as arterial puncture. This also caused the high rate of arterial puncture when using single-plane approach for FVC. The biplane approach allows for the visualization of the needle path in the long-axis view, as well as the needle tip, target vessel, and surrounding structures in the short-axis view, as long as the probe is positioned perpendicular to the course of the vessel. Even if the needle path cannot be clearly displayed in the long-axis view, the position of the needle tip can be visualized in the short-axis view to ensure that the needle is inserted into the vascular lumen. Using this technique, the needle tip can be observed directly, and its progression can be inferred from the movements of the surrounding tissues, even if minimal probe adjustments are required in rare cases. This could be the reason why a higher rate of first-puncture success and a shorter insertion time were achieved in the biplane approach than those in the single-plane approach in the present study.Previous researches have reported the efficacy and safety of US-guided venous catheterization using the biplane approach , 34, 35.The study results were obtained by five less-experienced operators, which might lead to a high rate of immediate complications, and thus cannot be directly extrapolated to sonographers with more experience. Further studies are required to assess the necessity of the x-plane approach for operators with prior experience. Moreover, the out-of-plane approach was not employed in this study. This is attributed to the use of the US-guided in-plane approach by less-experienced operators because it can real-time display the needle in-plane to ensure safety. In addition, subclavian vein was not included in this study because catheterization here is associated with higher mechanical complications and high technical difficulty which is difficult for less-experienced sonographers. Further studies including experienced operators and subclavian vein catheterization are necessary to confirm our findings.In critically ill patients, the US-guided CVC x-plane approach, when performed by a less experienced operator, shows some clinical advantages, such as a higher first-puncture success rate and fewer complications, with more confidence in the procedure. Moreover, the catheter insertion time was shorter in the x-plane approach than that in the single-plane approach.Additional file 1. Video S1. A 78-year female underwent the internal jugular vein catheterization using the x-plane approach.Additional file 2: Table S1. Ultrasonography characteristics of the study population.


The novel Coronavirus (COVID-19) has continued to present a significant burden to global public health efforts. The purpose of this study was to estimate the health-related quality of life, disability, and health status of individuals with self-reported long COVID at various lengths of recovery.We conducted a cross-sectional online survey of individuals with self-reported long COVID. Participants were asked to complete the five-item EuroQOL EQ-5D-5L and EQ visual analog scale, the 12-item World Health Organization Disability Assessment Schedule (WHODAS) 2.0 and the 10-item Patient Reported Outcome Measurement Information System (PROMIS) Global Health v1.2 short form. Descriptive and inferential statistics were used to characterize the responses and differences across groups.Eighty-two participants from 13 countries completed the EQ-5D-5L, 73 completed the WHODAS 2.0 and 80 participants completed the PROMIS. The mean EQ-5D-5L utility score was 0.51. The mean WHODAS score was 49.0. In the previous 30 days, participants reported their symptoms affected them for a mean of 24 days, they were totally unable to carry out usual activities for 15 days, and they cut back or reduced activities for 26 days. The mean PROMIS physical health and mental health scores were 10.7 and 8.6, respectively, corresponding to below-average health. No significant differences were detected across time or according to severity of acute infection.Long COVID presents a significant chronic health burden to adults in the US and abroad. This health burden may persist for many months post-acute infection.The online version contains supplementary material available at 10.1186/s41687-023-00572-0. Individuals with long COVID self-report persistently low levels of health-related quality of life, high levels of disability, and low levels of physical and mental health, many months post infection.There was no significant relationship detected between the self-reported severity of acute infection and the self-reported severity of long COVID symptoms.The online version contains supplementary material available at 10.1186/s41687-023-00572-0. The novel Coronavirus COVID-19) has continued to present a significant burden to global public health efforts with, as of October 2022, over 620 million cases worldwide ) or mild (N = 27/35 [77%]acute infections, which may be more susceptible to misclassification, indicated a positive COVID-19 or antibody test.Moreover, we used the definition of long COVID as defined by CDC, which comprises individuals with symptoms persisting for at least four weeks post-COVID infection. The WHO uses a much stricter definition, requiring symptoms at least three months post-infection that last for at least two months. Although it is possible that this sample may include some individuals who may not be eligible according to the WHO definition, we expect this to be minimal as individuals responded that they were, on average, 13 months beyond their acute infection.By using this convenience sample, it is possible we are misestimating the true health status of the long COVID population. Specifically, we may be overestimating disutility, disability, and underestimating health status as those who have recovered, either partially or fully, may no longer follow these social media support groups or may have not responded to the survey. Moreover, the relatively small sample prevented in-depth examinations of subgroups, such as those with asymptomatic acute infections, or differences in outcomes across countries and regions. The small sample also likely prevented us from statistically detecting clinically significant relationships. For example, the current analysis was powered to detect a change in utility of 0.29. For the largest change we saw across time, 0.14 units, our sample provided 24% power. Although a limitation for this study, the findings herein should provide a starting point for future research investigating these relationships.Although this study included individuals from 13 countries, these countries were concentrated in North America and Europe with inadequate representation from low- and middle-income countries. Additional investigations are needed to explore these trends and determine their generalizability to all individuals with long COVID.We used general health assessments in this study. By using general tools, we may be misestimating the true severity of the condition . As futuFinally, we did not collect information on the management of the acute COVID infection, such as pharmacotherapy use. These are important variables to explore given the relationship that infection severity has with likelihood of long COVID .Patients with long COVID are experiencing significant disutility, disability, and health impacts for many months after their initial illness. An awareness of the health impacts of long COVID may offer insights to providers and decision-makers as they seek to support individuals with long COVID. Continued efforts should be made to prevent disease transmission and the possible subsequent occurrence of long COVID.Additional file 1. Survey Questionnaire.